The introduction of antiretroviral therapy (ART) has resulted in significantly improved survival of AIDS patients and decreased incidence of HIV-associated dementia. But the activity of ART within the central nervous system (CNS) is still suboptimal. To address these shortcomings, we will develop drug-coated nanocrystals with the goal of delivering superior therapeutics for HIV treatment. We will demonstrate that a nanocrystal (i.e. 2 nm - 10 nm diameter inorganic crystal) can serve as a base scaffold to allow us to overcome several of the limitations of current ART. The size of the nanocrystal will allow both the ability to efficiently disrupt protein/protein interactions, and can be fabricated with a combination of molecules of an array of properties on the nanocrystal surface. We will place targeting molecules such as glucose derivatives onto the surface of the gold nanocrystal to deliver potent antivirals such as integrase inhibitors across the blood-brain barrier and into the CNS. Specific Aim 1: A multifuctional hybrid nanocrystal with antiviral and targeting functions can be designed and synthesized. Specific Aim 2: Drug-nanocrystal conjugates can be optimized for the density of drug molecules on the nanocrystal surface, crystal diameter, and conjugate stability. Specific Aim 3: Nanocrystals will cross the blood-brain barrier (BBB) and inhibit HIV replication. We hypothesize that nanocrystal-based therapeutics will serve as an adjunct to current ART in selected clinical situations where improved delivery of therapeutic molecules to specific tissues or anatomical or cellular compartments is required. The history of the use of gold salts in rheumatoid disease suggests that long-term toxicities, if encountered, may be manageable. As proof of concept, we will develop and test nanocrystal systems to deliver ART across the blood-brain barrier, to meet this important medical need. PUBLIC HEALTH RELEVANCE: Highly active antiretroviral therapy (ART) has led to a significant decrease in the morbidity and mortality of HIV- infected individuals, but poor penetration of ART into the CNS allows continued HIV replication in the CNS. Our approach to target the CNS aims to take advantage of the chemical pliability of gold nanocrystals, allowing them to be armed with chemical moieties that confer antiviral properties and allow the crystals to access the CNS. We will test novel nanotherapeutics in cell culture and animal model systems of the blood-brain barrier and of HIV infection.